Seeking Autism’s Biochemical Roots

The biochemist Ricardo E. Dolmetsch has pioneered a major shift in autism research, largely putting aside behavioral questions to focus on cell biology and biochemistry.

Dr. Dolmetsch, 45, has done most of his work at Stanford. Since our interviews — a condensed and edited version of which follows — he has taken a leave to join Novartis, where his mission is to organize an international team to develop autism therapies.

“Pharmaceutical companies have financial and organizational resources permitting you to do things you might not be able to do as an academic,” he said. “I really want to find a drug.”

Q. Did you start out your professional life studying the biochemistry of autism?

A. No. In graduate school and as a postdoc, I’d done basic research on the ion channels on the membranes of cells. By my mid-20s, I had my name on some high-profile papers.

Then, around 2006, my son who was then 4 was diagnosed with autism. We had suspected it. He didn’t talk much, was hyperactive, very moody. He assembled huge towers based on the color spectrum. He did all sorts of things that were very unusual.

Given the signs, why did you wait that long to seek a diagnosis?

I’m from Latin America [Cali, Colombia], and my Latin thing was, “This is the way boys are.” But he would just scream for hours and hours, uncontrollable. He didn’t sleep. We didn’t understand it. After a while, his teachers said, “You probably ought to have him seen.” So we went to a psychiatrist and neurologist and ultimately we got differing diagnoses.

This is how child psychiatry is: It is diagnosis by questionnaire. If you go to a different specialists, you get different answers.

Autism, it turns out, is a whole bunch of diseases, clumped into one big group. After many confusing months, we finally heard “autism.” My response immediately was: “We’re not going to leave any stone unturned to help him.”

It turned out, however, that there weren’t many medical things to be done. There are behavioral approaches which can improve things, though none are a cure. Once we understood this, I started really changing the direction of my lab to things more directed towards autism and neurodevelopmental diseases. These include childhood epilepsy, fragile X syndrome and schizophrenia.

So fate chose your research topic for you?

I don’t believe in “fate.” There was motivation. I started reading and realized the one big change that could give autism research some traction was the genetics revolution. Because of it, we can now identify gene mutations associated with the neurodevelopmental diseases — there are about 800 different mutations associated with autism. What’s missing, in most cases, is an understanding of what the mutations do so that we might then alter the molecular biology of the nervous system’s cells to make them function more normally.

The animal models — so effective in finding treatments for other types of diseases — are not always helpful here. For the best results, you need to study actual human tissue.

That got me thinking about cancer, where there’s been a revolution in treatment. When you get breast cancer — which like autism isn’t one disease — the tumor is molecularly characterized to help oncologists understand what specific cancer you have and what sort of treatments will work against it. Could we find something similar for the neurodevelopmental diseases?

With breast cancer, pathologists can biopsy diseased tissue to look at the patient’s genetics and order treatments based on what they find. There’s no way to obtain brain tissue samples from living children with autism. Is this a stumbling block for your research?

Yes. But there’s a way around it. Shinya Yamanaka [who won the 2012 Nobel Prize in Physiology or Medicine] has been reprogramming human skin cells to become stem cells and thus all kinds of other cells, including the cells of the nervous system. Thanks to him, we can now make nerve cells that look like the neurons of a human embryo. If you could take skin cells from an autistic child and turn them into neurons, we might be able to understand what kind of autism the child has and what chemical fixes might help.

Your wife, Asha Nigh, is a neurobiologist. How did your son’s diagnosis affect her research?

She can’t work full time any more. She’s earned a Ph.D. in insurance. When you have an autistic child, you must learn how to navigate the elaborate, complicated medical system in the U.S. That requires a lot of time. Even when you have good insurance, much of what your child needs isn’t covered. You need behavioral help, special help to train the child in language, social skills, everything.

This is going to sound terribly sexist — my mother, who is a great feminist, is going to kill me for saying this — but I sometimes tell my wife, “I’m having the career for both of us.” Of course, that is totally lame.

For your research, you need children with different types of autism. How do you find them?

Through social media. We’re often interested in groups or families who have specific kinds of mutations. Some of them are rare — 5,000 people worldwide.

So we have a committee that decides what’s the next mutation we’re going to work on. Then we find children with it. It used to be we’d spend half of our budget locating people. Now, we go to the families with a Facebook page for people with X, Y, or Z mutation. Then I’ll post a call. Parents will come forward.

The aim is to develop a database of the mutations we think are causative of the neuropsychiatric diseases. If we can get samples through stem-cell-derived neurons and create a library of them, we could change the way the diseases are diagnosed.

You do a lot of fieldwork with actual patients — going to their homes, meeting them. That’s unusual with an investigator doing basic science. Why do it?

You get a lot of information when you actually talk to parents. There’s one kind of epilepsy, for example, where girls get seizures in these clusters, and the clusters appear to be synchronized with hormonal cycles. I would never know that had I not talked to the families — it doesn’t appear in the literature. But it turns out to be very informative because then it tells you the defect must be regulated by hormones, which means that if we can figure out what the hormones do, we’ll get to what the defect might be.

I’m convinced this research is most effective when you start with the patients. Many of my colleagues study animals, but we are much, much better at figuring out what is wrong with humans because we have evolved to pick up strangeness in affect. We have evolved to notice patterns.

Another thing: I find that meeting families is motivating. There is a big difference between working on some sort of associated mutation and actually meeting somebody affected.

A version of this article appears in print on , on Page D2 of the New York edition with the headline: Seeking Autism’s Biochemical Roots. Order Reprints | Today’s Paper | Subscribe